Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: Effect of liver transplantation

Diabetes mellitus frequently complicates cirrhosis but the pathogenic mecha nisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic-diabetic patients waiting for liver transplant bec ause of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the beta-cell function and an insulin clamp combined with [3-H-3]glucose infusion to measure whole body glucose metabolism befo re and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a pr ofound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P < .05) and insulin deficiency during the O GTT (P < .05), Liver transplantation normalized endogenous glucose producti on and insulin sensitivity but failed to cure diabetes in 8 of the 24 patie nts because a markedly low insulin response during the OGTT Age, body mass index, family history of diabetes, immunosuppressive drugs, and pathogenesi s of cirrhosis did not predict in whom liver transplant was going to cure d iabetes. On the contrary, a reduced secretory response characterized the pa tients in whom the transplant would not be curative. In summary, insulin re sistance was a primary event complicating cirrhosis but additional beta-cel l secretory defects were crucial for development of diabetes. Liver transpl antation, lessening insulin resistance, cured hepatogenous diabetes in 67% of cirrhotic-diabetic patients; nevertheless 33% were still diabetics becau se the persistence of a reduced beta-cell function, which makes these patie nts eventually eligible for combined islet transplantation.